Hematopoietic stem cells (HSCs) give rise to all blood lineages1. As HSCs differentiate along one lineage, they gradually lose the ability to develop into other lineages2. Hematopoietic differentiation involves lineage commitment, defined here as the initiation of developmental program(s) that lead to a particular cell fate. The accompanying inability to differentiate into other lineages has been referred to as lineage maintenance3. Lineage commitment and lineage maintenance are complementary processes that guide cell fate decisions. Thus, cells committed to a particular lineage have alternative developmental choices until lineage maintenance is complete4.
Hematopoietic differentiation has been schematically depicted as a “tree of hematopoiesis”, outlining the possible developmental choices. According to this prevailing schema, the decision between lymphoid and myeloid lineages occurs very early. However, alternative views have been proposed, including the existence of a common myelo-lymphoid progenitor5-6. Elucidation of hematopoietic developmental pathways and extrinsic stimuli that influence them is instrumental to understanding both normal and malignant hematopoiesis. In particular, factors that favor natural killer (NK) cell development could be used to exploit their activity against malignancies.
NK cells are innate immune effector cells. Their derivation from either lymphoid or myeloid lineages was debated early in their discovery. Further research showed that NK cells can be derived from common lymphoid progenitors (CLPs) and hence have been considered separate from myeloid lineage8-9.
Human secondary lymphoid tissues (SLTs) contain IL-22 producing cells with an immature NK phenotype. The study of human IL-22 producing NK lineage cells is limited by their location in SLT. Accordingly, investigators use small quantities of material obtained from either aborted fetal tissue or surgical specimens, potentially in the setting of pathology.